System and method for distinguishing among cardiac ischemia, hypoglycemia and hyperglycemia using an implantable medical device

ABSTRACT

Techniques are described for detecting ischemia, hypoglycemia or hyperglycemia based on intracardiac electrogram (IEGM) signals. Ischemia is detected based on a shortening of the interval between the QRS complex and the end of a T-wave (QTmax), alone or in combination with a change in ST segment elevation. Alternatively, ischemia is detected based on a change in ST segment elevation combined with minimal change in the interval between the QRS complex and the end of the T-wave (QTend). Hypoglycemia is detected based on a change in ST segment elevation along with a lengthening of either QTmax or QTend. Hyperglycemia is detected based on a change in ST segment elevation along with minimal change in QTmax and in QTend. By exploiting QTmax and QTend in combination with ST segment elevation, changes in ST segment elevation caused by hypo/hyperglycemia can be properly distinguished from changes caused by ischemia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is related to copending U.S. patent applications: 1)Ser. No. 11/043,780, titled “System and Method for Distinguishing AmongCardiac Ischemia, Hypoglycemia and Hyperglycemia using an ImplantableMedical Device”; and 2) Ser. No. 11/043,804, tilted “System and Methodfor Distinguishing Among Cardiac Ischemia, Hypoglycemia andHyperglycemia using an Implantable Medical Device”, all applicationsfiled concurrently herewith.

FIELD OF THE INVENTION

The invention generally relates to implantable medical devices such aspacemakers and implantable cardioverter/defibrillators (ICDs) and, inparticular, to techniques for detecting cardiac ischemia, hypoglycemiaand hyperglycemia using such devices.

BACKGROUND

Cardiac ischemia is a condition whereby heart tissue does not receiveadequate amounts of oxygen and is usually caused by a blockage of anartery leading to heart tissue. If sufficiently severe, cardiac ischemiaresults in an acute myocardial infarction (AMI), also referred to as aheart attack. With AMI, a substantial portion of heart muscle ceases tofunction because it no longer receives oxygen, usually due tosignificant blockage of the coronary artery. Generally, AMI occurs whenplaque (such as fat, cholesterol, and calcium) builds up and thenruptures in the coronary artery, allowing a blood clot or thrombus toform. Eventually, the blood clot completely blocks the coronary arteryand so heart tissue beyond the blockage no longer receives oxygen andthe tissue dies. In many cases, an AMI proves fatal because too muchtissue is damaged to allow continued functioning of the heart muscle.Indeed, AMI is a leading cause of death here in the United States andworldwide. In other cases, although the AMI itself is not fatal, itstrikes while the victim is engaged in potentially dangerous activities,such as driving vehicles or flying airplanes, and the severe pain andpossible loss of consciousness associated with AMI results in fatalaccidents. Even if the victim survives the AMI, quality of life maythereafter be severely restricted.

Often AMI is preceded by episodes of cardiac ischemia that are notsufficiently serious to cause actual permanent injury to the hearttissue. Nevertheless, these episodes are often precursors to AMI.Episodes of cardiac ischemia may also trigger certain types ofarrhythmias that may prove fatal, particularly ventricular fibrillation(VF) wherein the ventricles of the heart beat chaotically, resulting inlittle or no net flow of blood from the heart to the brain and otherorgans. Indeed, serious episodes of cardiac ischemia (referred to hereinas acute myocardial ischemia) typically result in either a subsequentAMI or VF, often within one to twenty-four four hours, sometimes withinonly a half an hour or less. Accordingly, it would be highly desirableto provide a technique for reliably detecting acute myocardial ischemiaso that the victim may be warned and medical attention sought. Ifproperly warned, surgical procedures may be implemented to locate andremove the growing arterial blockage or anti-thrombolytic medicationsmay be administered. At the very least, advanced warning would allow thevictim to cease activities that might result in a fatal accident.Moreover, in many cases, AMI or VF is triggered by strenuous physicalactivities and so advanced warning would allow the victim to cease suchactivities, possibly preventing AMI or VF from occurring.

Many patients at risk of cardiac ischemia have pacemakers, ICDs or othermedical devices implanted therein. Accordingly, techniques have beendeveloped for detecting cardiac ischemia using implanted medicaldevices. In particular, techniques have been developed for analyzingintracardiac electrogram (IEGM) signals in an effort to detect cardiacischemia. See, as examples, the following U.S. Patents: U.S. Pat. No.5,113,869 to Nappholz; U.S. Pat. No. 5,135,004 to Adams et al.; U.S.Pat. No. 5,199,428 to Obel et al.; U.S. Pat. No. 5,203,326 to Collins;U.S. Pat. No. 5,313,953 to Yomtov et al; U.S. Pat. No. 6,501,983 toNatarajan, et al.; U.S. Pat. Nos. 6,016,443, 6,233,486, 6,256,538, and6,264,606 to Ekwall; U.S. Pat. No. 6,021,350 to Mathson; U.S. Pat. Nos.6,112,116 and 6,272,379 to Fischell et al; U.S. Pat. Nos. 6,128,526,6,115,628 and 6,381,493 to Stadler et al; and U.S. Pat. No. 6,108,577 toBenser. Most IEGM-based ischemia detection techniques seek to detectischemia by identifying changes in the elevation of the ST segment ofthe IEGM that occur during cardiac ischemia. The ST segment representsthe portion of the cardiac signal between ventricular depolarization(also referred to as an R-wave or QRS complex) and ventricularrepolarization (also referred to as a T-wave). The QRS complex usuallyfollows an atrial depolarization (also referred to as a P-wave.)Strictly speaking, P-waves, R-waves and T-waves are features of asurface electrocardiogram (EKG). For convenience and generality, hereinthe terms R-wave, T-wave and P-wave are used to refer to thecorresponding internal signal component as well.

A significant concern with any cardiac ischemia detection technique thatrelies on changes in the ST segments is that systemic influences withinthe patient can alter the ST segment. For example, hypoglycemia (lowblood sugar levels) and hyperglycemia (high blood sugar levels) can bothaffect ST segment deviation. In addition, electrolyte imbalance, such ashypokalemia (low potassium levels) or hyperkalemia (high potassiumlevels) can affect the ST segment. Certain anti-arrhythmic drugs canalso affect the ST-segment.

Accordingly, alternative techniques for detecting cardiac ischemia havebeen developed, which do not rely on ST segment elevation. One suchtechnique is set forth in U.S. patent application Ser. No. 10/603,429,entitled “System And Method For Detecting Cardiac Ischemia Using AnImplantable Medical Device,” of Wang et al., filed Jun. 24, 2003, whichis incorporated by reference herein. Rather than examine the ST segment,the technique of Wang et al. instead examines post-T-wave segments, i.e.that portion of the cardiac signal immediately following the T-wave. Inone example, the onset of cardiac ischemia is identified by detecting asharp falling edge within post-T-wave signals. A warning is thenprovided to the patient. The warning preferably includes both aperceptible electrical notification signal applied directly tosubcutaneous tissue and a separate warning signal delivered viashort-range telemetry to a handheld warning device external to thepatient. After the patient feels the internal warning signal, he or sheholds the handheld device near the chest to receive the short-rangetelemetry signal, which provides a textual warning. The handheld warningdevice thereby provides confirmation of the warning to the patient, whomay be otherwise uncertain as to the reason for the internally generatedwarning signal. Another technique for detecting cardiac ischemia basedon T-waves is set forth in U.S. patent application Ser. No. 10/603,398,entitled “System And Method For Detecting Cardiac Ischemia Based OnT-Waves Using An Implantable Medical Device,” of Min et al., filed Jun.24, 2003, which is also incorporated by reference herein. With thetechnique of Min et al., cardiac ischemia is detected based either onthe total energy of the T-wave or on the maximum slope of the T-wave.Again, if ischemia is detected, a warning signal is provided to thepatient.

Hence, various cardiac ischemia detection techniques have been developedthat exploit T-waves. Although these techniques are effective, it wouldbe desirable to provide still other T-wave-based ischemia detectiontechniques and it is to that end that aspects of the present inventionare directed. It would also be desirable to provide techniques thatexploit deviations in the ST segment as well as changes in T-waves toprovide further improvements in cardiac ischemia detection.

In particular, it would be highly desirable to identify particularchanges in T-waves that can be used to distinguish deviations in the STsegment caused by cardiac ischemia from changes caused by hypoglycemiaor hyperglycemia or other systemic affects so as to improve thereliability and specificity of ST segment-based ischemia detection. Itis to this end that other aspects of the invention are directed.

Although the detection of cardiac ischemia is of paramount importancesince an ischemia may be a precursor to a potentially fatal AMI or VF,it is also desirable to detect hypoglycemia or hyperglycemia so as toprovide suitable warning signals and still other aspects of theinvention are directed to that end. Diabetic patients, particular, needto frequently monitor blood glucose levels to ensure that the levelsremain within acceptable bounds and, for insulin dependent diabetics, todetermine the amount of insulin that must be administered. Conventionaltechniques for monitoring blood glucose levels, however, leave much tobe desired. One conventional technique, for example, requires that thepatient draw blood, typically by pricking the finger. The drawn blood isthen analyzed by a portable device to determine the blood glucose level.The technique can be painful and therefore can significantly discouragethe patient from periodically checking blood glucose levels. Moreover,since an external device is required to analyze the blood, there is therisk that the patient will neglect to keep the device handy, preventingperiodic blood glucose level monitoring. For insulin-dependentdiabetics, failure to properly monitor blood glucose levels can resultin improper dosages of insulin causing, in extreme cases, severe adversehealth consequences such as a ketoacidotic diabetic coma, which can befatal. Accordingly, there is a significant need to provide a reliablehypo/hyperglycemia detection technique, which does not rely on thepatient to monitoring his or her own glucose levels and which does notrequire an external analysis device.

In view of the many disadvantages of conventional external blood glucosemonitoring techniques, implantable blood glucose monitors have beendeveloped, which included sensors for mounting directly within the bloodstream. However, such monitors have not achieved much success as theglucose sensors tend to clog over very quickly. Thus, an implantabledevice that could continually and reliably measure blood glucose levelswithout requiring glucose sensors would be very desirable. Moreover, aswith any implantable device, there are attended risks associated withimplanting the blood glucose monitor, such as adverse reactions toanesthetics employed during the implantation procedure or the onset ofsubsequent infections. Hence, it would be desirable to provide forautomatic hypo/hyperglycemia detection using medical devices that wouldotherwise need to be implanted anyway, to thereby minimize the risksassociated with the implantation of additional devices. In particular,for patients already requiring implantation of a cardiac stimulationdevice, such as a pacemaker or ICD, it would be desirable to exploitfeatures of electrical cardiac signals, particularly ST segments andT-waves, for use in detecting hypo/hyperglycemia and still other aspectsof the invention are directed to that end.

SUMMARY

In accordance with a first illustrative embodiment, various techniquesare provided for use with an implantable medical device for detectingcardiac ischemia.

In a first exemplary cardiac ischemia detection technique, the devicetracks changes over time in the length of an interval between thebeginning of a QRS complex and the maximum amplitude (i.e. the peak) ofa corresponding T-wave. This repolarization peak-based interval isreferred to herein as QTmax. A change in the interval is referred to asΔQTmax. The device detects the onset of myocardial ischemia based on anysignificant shortening of QTmax. A change in the length of QTmax isbelieved to be a reliable indicator of cardiac ischemia. Moreover, QTmaxalso provides a convenient means for distinguishing changes in the IEGMdue to hyper/hypoglycemia from changes due to cardiac ischemia. Whereascardiac ischemia causes a shortening of QTmax, hypoglycemia causes alengthening. Hyperglycemia causes little or no change. Preferably, thedevice also exploits ST segment deviation to improve detectionspecificity. Cardiac ischemia typically causes a change in ST segment.Hence, if a significant deviation in the ST segment is detected alongwith a shortening of QTmax, the detection of cardiac ischemia based onQTmax is confirmed. Note that QRS complexes are electrical cardiacsignals representative of depolarization or “activation” of theventricles; whereas T-waves are electrical cardiac signalsrepresentative of repolarization or “deactivation” of the ventricles.Hence, a QRS complex is a ventricular depolarization event or aventricular activation event. A T-wave is a ventricular repolarizationevent or a ventricular deactivation event. These alternative terms areused herein for generality where appropriate.

In a second exemplary cardiac ischemia detection technique, the devicetracks changes over time in the ST segment and in the length of theinterval between the beginning of a QRS complex and the end of acorresponding T-wave. This repolarization end-based interval is referredto herein as QTend. A change in the interval is referred to as ΔQTend. Achange in the ST segment is referred to as ST deviation. The device thendetects the onset of a myocardial ischemia based on any significant STdeviation occurring along with a lack of significant change in QTend,i.e. ΔQTend is nearly zero. In this regard, QTend provides a convenientmeans for distinguishing changes in the IEGM due to hypoglycemia fromchanges due to cardiac ischemia. Whereas cardiac ischemia causes littleor no change in QTend, hypoglycemia causes a substantial lengthening ofQTend. Hence, a significant ST deviation, which might otherwise bemisinterpreted as an indication of ischemia, is instead properlyinterpreted as an indication of hypoglycemia if a substantial change inQTend is also observed. Hyperglycemia, on the other hand, causes a STsegment deviation but does not typically cause a significant change inQTend.

Preferably, the device tracks ST deviation and both QTmax and QTend toprovide further specificity. A significant deviation in the ST segmentcombined with a shortening of QTmax and little or no change in QTend isindicative of cardiac ischemia. A significant deviation in the STsegment combined with a lengthening of both QTmax and QTend isindicative of hypoglycemia. A significant deviation in the ST segmentcombined with little or no change in QTmax and also little or no changein QTend is indicative of hyperglycemia. A lack of significant deviationin the ST segment indicates a lack of ischemia, hypoglycemia orhyperglycemia, i.e. that the patient is normal, at least insofar asthese conditions are concerned. Accordingly, it may be preferable tofirst examine the ST segment before proceeding to examine QTmax andQTend.

In accordance with a second aspect of the invention, techniques areprovided for use with an implantable medical device for detectinghypoglycemia. In an exemplary embodiment, the device tracks changes overtime in QTmax and/or QTend. The device then detects the onset of ahypoglycemia based on any significant lengthening of QTmax and/or QTend.Preferably, the device also uses deviations in the ST segment to improvedetection specificity. As noted, hypoglycemia typically causes asignificant ST deviation. Hence, if a significant ST deviation isdetected along with a lengthening of QTmax or QTend, the detection ofhypoglycemia is confirmed. To provide increased specificity, STdeviation, QTmax and QTend are preferably all used. Otherwiseconventional hypo/hyperglycemia detection parameters may be used as wellto further optimize detection specificity/sensitivity.

In accordance with a third aspect of the invention, various techniquesare provided for use with an implantable medical device for detectinghyperglycemia. In an exemplary embodiment, the device tracks deviationsin the ST segment and in QTmax. The device then detects the onset of ahyperglycemia based on any significant ST deviation combined with littleor no change in QTmax. As noted, hyperglycemia typically causes asignificant deviation in the ST segment but causes little or no changein QTmax, whereas cardiac ischemia causes a significant deviation in theST segment along with a significant reduction in QTmax. QTend may alsobe examined to provide corroboration. There is also little or no changein QTend during hyperglycemia.

The following table summarizes changes in the ST segment, QTmax andQTend in response to cardiac ischemia, hypoglycemia, and hyperglycemiathat are exploited by the invention.

TABLE I ST Segment QTmax QTend Ischemia Significant Shortens Little orno deviation change Hypoglycemia Significant Lengthens Lengthensdeviation Hyperglycemia Significant Little or no Little or no deviationchange change Normal No significant No significant No significantdeviation deviation deviation

Upon detecting of the onset of an cardiac ischemia, hypoglycemia orhyperglycemia, appropriate warning signals are generated, which includeboth “tickle warning” signals applied to subcutaneous tissue and shortrange telemetry warning signals transmitted to a device external to thepatient. In one example, once the tickle warning is felt, the patientpositions an external warning device above his or her chest. Thehandheld device receives the short-range telemetry signals and providesaudible or visual verification of the warning signal. The handheldwarning device thereby provides confirmation of the warning to thepatient, who may be otherwise uncertain as to the reason for theinternally generated warning signal.

Therapy may also be initiated or modified. In this regard, pacingtherapy may be modified in response to the detected medical conditionor, if the device is equipped with a drug pump, appropriate medicationsmay be administered. For ischemia, anti-thrombolytic drugs may bedelivered. For hypo/hyperglycemia, insulin may be regulated. Inaddition, if the device is an ICD, it may be controlled to immediatelybegin charging defibrillation capacitors up on detection of ischemia soas to permit prompt delivery of a defibrillation shock, which may beneeded if the ischemia triggers VF. Additionally, or in the alternative,values indicative of ST deviation, QTmax and/or QTend may be stored fordiagnostic purposes. In this regard, the device may calculate an“ischemic burden”, which is representative of the risk of ischemia andis derived from ST deviation, QTmax and/or QTend.

Hence, improved techniques are provided both for reliably detectingcardiac ischemia, hypoglycemia and hyperglycemia and for distinguishingtherebetween. The techniques are preferably performed by the implantedmedical device itself so as to provide prompt warnings of ischemia,hypoglycemia or hyperglycemia. Alternatively, the techniques may beperformed by external devices, such as bedside monitors or the like,based on IEGM signals detected by an implanted device and transmitted tothe external device.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the invention may be more readilyunderstood by reference to the following description taken inconjunction with the accompanying drawings, in which:

FIG. 1 is a simplified diagram illustrating an implantable stimulationdevice with at least three leads implanted in the heart of a patient fordelivering multi-chamber stimulation and shock therapy;

FIG. 2 is a functional block diagram of the implantable cardiacstimulation device of FIG. 1 illustrating basic elements of thestimulation device, particularly illustrating components for detectingcardiac ischemia, hypoglycemia, and hyperglycemia based on variouscombinations of QTmax, QTend and ST deviation;

FIG. 3 is a flow chart providing an overview of an exemplary methodperformed by the device of FIG. 2 for detecting cardiac ischemia basedon a reduction in QTmax;

FIG. 4 is a graph providing a stylized representation of the IEGM of asingle heartbeat, particularly illustrating the QTmax interval;

FIG. 5 is a graph providing exemplary representations of the IEGM of asingle heart beat, particularly illustrating a reduction in the QTmaxinterval caused by cardiac ischemia;

FIG. 6 is a flow chart providing an overview of an exemplary methodperformed by the device of FIG. 2 for detecting cardiac ischemia basedprimarily on a significant deviation in the ST segment along with littleor no change in the QTend interval;

FIG. 7 is a graph providing a stylized representation of the IEGM of asingle heartbeat, particularly illustrating ST deviation and the QTendinterval;

FIG. 8 is a graph providing exemplary representations of the IEGM of asingle heart beat, particularly illustrating a significant deviation inthe ST segment caused by cardiac ischemia, along with a lack of changein QTend;

FIG. 9 is a flow chart providing an overview of an exemplary methodperformed by a hypoglycemia detection system of FIG. 2 for detectinghypoglycemia based primarily on a significant lengthening of eitherQTmax or QTend;

FIG. 10 is a graph providing exemplary representations of the IEGM of asingle heartbeat, particularly illustrating a significant lengthening ofboth QTmax and QTend;

FIG. 11 is a flow chart providing an overview of an exemplary methodperformed by a hyperglycemia detection system of FIG. 2 for detectinghyperglycemia based primarily on a significant deviation in the STsegment along with little or no change in QTmax;

FIG. 12 is a graph providing exemplary representations of the IEGM of asingle heart beat, particularly illustrating a significant deviation inST segment caused by hyperglycemia, along with little or no change inQTmax;

FIG. 13 is a flow chart providing an overview of an exemplary methodperformed by the implantable device of FIG. 2 for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on ST segment,QTmax, and QTend;

FIG. 14 is a flow chart providing an overview of an exemplary methodperformed by the implantable device of FIG. 2 for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on ST segmentdeviation and QTmax; and

FIG. 15 is a flow chart providing an overview of an exemplary methodperformed by the implantable device of FIG. 2 for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on ST segmentdeviation and QTend.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following description includes the best mode presently contemplatedfor practicing the invention. The description is not to be taken in alimiting sense but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe ascertained with reference to the issued claims. In the descriptionof the invention that follows, like numerals or reference designatorswill be used to refer to like parts or elements throughout.

Overview of Implantable Device

As shown in FIG. 1, there is a stimulation device 10 in electricalcommunication with the heart 12 of a patient by way of three leads, 20,24 and 30, suitable for delivering multi-chamber stimulation and shocktherapy. To sense atrial cardiac signals and to provide right atrialchamber stimulation therapy, the stimulation device 10 is coupled to animplantable right atrial lead 20 having at least an atrial tip electrode22, which typically is implanted in the right atrial appendage and anatrial ring electrode 23. To sense left atrial and ventricular cardiacsignals and to provide left chamber pacing therapy, the stimulationdevice 10 is coupled to a “coronary sinus” lead 24 designed forplacement in the “coronary sinus region” via the coronary sinus or forpositioning a distal electrode adjacent to the left ventricle and/oradditional electrode(s) adjacent to the left atrium. As used herein, thephrase “coronary sinus region” refers to the vasculature of the leftventricle, including any portion of the coronary sinus, great cardiacvein, left marginal vein, left posterior ventricular vein, middlecardiac vein, and/or small cardiac vein or any other cardiac veinaccessible by the coronary sinus. Accordingly, an exemplary coronarysinus lead 24 is designed to receive atrial and ventricular cardiacsignals and to deliver left ventricular pacing therapy using at least aleft ventricular tip electrode 26, left atrial pacing therapy using atleast a left atrial ring electrode 27, and shocking therapy using atleast a left atrial coil electrode 28.

The stimulation device 10 is also shown in electrical communication withthe heart by way of an implantable right ventricular lead 30 having, inthis embodiment, a right ventricular tip electrode 32, a rightventricular ring electrode 34, a right ventricular (RV) coil electrode36, and an SVC coil electrode 38. Typically, the right ventricular lead30 is transvenously inserted into the heart so as to place the rightventricular tip electrode 32 in the right ventricular apex so that theRV coil electrode is positioned in the right ventricle and the SVC coilelectrode 38 is positioned in the superior vena cava. Accordingly, theright ventricular lead 30 is capable of receiving cardiac signals, anddelivering stimulation in the form of pacing and shock therapy to theright ventricle. To provide a “tickle warning” signal, an additionalelectrode 31 is provided in proximity to the device can.

As illustrated in FIG. 2, a simplified block diagram is shown of themulti-chamber implantable stimulation device 10, which is capable oftreating both fast and slow arrhythmias with stimulation therapy,including cardioversion, defibrillation, and pacing stimulation. While aparticular multi-chamber device is shown, this is for illustrationpurposes only, and one of skill in the art could readily duplicate,eliminate or disable the appropriate circuitry in any desiredcombination to provide a device capable of treating the appropriatechamber(s) with cardioversion, defibrillation and pacing stimulation.

The housing 40 for the stimulation device 10, shown schematically inFIG. 2, is often referred to as the “can”, “case” or “case electrode”and may be programmably selected to act as the return electrode for all“unipolar” modes. The housing 40 may further be used as a returnelectrode alone or in combination with one or more of the coilelectrodes, 28, 36 and 38, for shocking purposes. The housing 40 furtherincludes a connector (not shown) having a plurality of terminals, 42,43, 44, 46, 48, 52, 54, 56 and 58 (shown schematically and, forconvenience, the names of the electrodes to which they are connected areshown next to the terminals). As such, to achieve right atrial sensingand pacing, the connector includes at least a right atrial tip terminal(A_(R) TIP) 42 adapted for connection to the atrial tip electrode 22 anda right atrial ring (A_(R) RING) electrode 43 adapted for connection toright atrial ring electrode 23. To achieve left chamber sensing, pacingand shocking, the connector includes at least a left ventricular tipterminal (V_(L) TIP) 44, a left atrial ring terminal (A_(L) RING) 46,and a left atrial shocking terminal (A_(L) COIL) 48, which are adaptedfor connection to the left ventricular ring electrode 26, the leftatrial tip electrode 27, and the left atrial coil electrode 28,respectively. To support right chamber sensing, pacing and shocking, theconnector further includes a right ventricular tip terminal (V_(R) TIP)52, a right ventricular ring terminal (V_(R) RING) 54, a rightventricular shocking terminal (R_(V) COIL) 56, and an SVC shockingterminal (SVC COIL) 58, which are adapted for connection to the rightventricular tip electrode 32, right ventricular ring electrode 34, theRV coil electrode 36, and the SVC coil electrode 38, respectively. Toprovide the “tickle warning” signal, an additional terminal 59 isprovided for connection to the tickle warning electrode 31 of FIG. 1.

At the core of the stimulation device 10 is a programmablemicrocontroller 60, which controls the various modes of stimulationtherapy. As is well known in the art, the microcontroller 60 (alsoreferred to herein as a control unit) typically includes amicroprocessor, or equivalent control circuitry, designed specificallyfor controlling the delivery of stimulation therapy and may furtherinclude RAM or ROM memory, logic and timing circuitry, state machinecircuitry, and I/O circuitry. Typically, the microcontroller 60 includesthe ability to process or monitor input signals (data) as controlled bya program code stored in a designated block of memory. The details ofthe design and operation of the microcontroller 60 are not critical tothe invention. Rather, any suitable microcontroller 60 may be used thatcarries out the functions described herein. The use ofmicroprocessor-based control circuits for performing timing and dataanalysis functions are well known in the art.

As shown in FIG. 2, an atrial pulse generator 70 and a ventricular pulsegenerator 72 generate pacing stimulation pulses for delivery by theright atrial lead 20, the right ventricular lead 30, and/or the coronarysinus lead 24 via an electrode configuration switch 74. It is understoodthat in order to provide stimulation therapy in each of the fourchambers of the heart, the atrial and ventricular pulse generators, 70and 72, may include dedicated, independent pulse generators, multiplexedpulse generators or shared pulse generators. The pulse generators, 70and 72, are controlled by the microcontroller 60 via appropriate controlsignals, 76 and 78, respectively, to trigger or inhibit the stimulationpulses.

The microcontroller 60 further includes timing control circuitry 79which is used to control the timing of such stimulation pulses (e.g.,pacing rate, atrio-ventricular (AV) delay, atrial interconduction (A-A)delay, or ventricular interconduction (V-V) delay, etc.) as well as tokeep track of the timing of refractory periods, blanking intervals,noise detection windows, evoked response windows, alert intervals,marker channel timing, etc., which is well known in the art. Switch 74includes a plurality of switches for connecting the desired electrodesto the appropriate I/O circuits, thereby providing complete electrodeprogrammability. Accordingly, the switch 74, in response to a controlsignal 80 from the microcontroller 60, determines the polarity of thestimulation pulses (e.g., unipolar, bipolar, combipolar, etc.) byselectively closing the appropriate combination of switches (not shown)as is known in the art.

Atrial sensing circuits 82 and ventricular sensing circuits 84 may alsobe selectively coupled to the right atrial lead 20, coronary sinus lead24, and the right ventricular lead 30, through the switch 74 fordetecting the presence of cardiac activity in each of the four chambersof the heart. Accordingly, the atrial (ATR. SENSE) and ventricular (VTR.SENSE) sensing circuits, 82 and 84, may include dedicated senseamplifiers, multiplexed amplifiers or shared amplifiers. The switch 74determines the “sensing polarity” of the cardiac signal by selectivelyclosing the appropriate switches, as is also known in the art. In thisway, the clinician may program the sensing polarity independent of thestimulation polarity. Each sensing circuit, 82 and 84, preferablyemploys one or more low power, precision amplifiers with programmablegain and/or automatic gain control, bandpass filtering, and a thresholddetection circuit, as known in the art, to selectively sense the cardiacsignal of interest. The automatic gain control enables the device 10 todeal effectively with the difficult problem of sensing the low amplitudesignal characteristics of atrial or ventricular fibrillation. Theoutputs of the atrial and ventricular sensing circuits, 82 and 84, areconnected to the microcontroller 60 which, in turn, are able to triggeror inhibit the atrial and ventricular pulse generators, 70 and 72,respectively, in a demand fashion in response to the absence or presenceof cardiac activity in the appropriate chambers of the heart.

For arrhythmia detection, the device 10 utilizes the atrial andventricular sensing circuits, 82 and 84, to sense cardiac signals todetermine whether a rhythm is physiologic or pathologic. As used herein“sensing” is reserved for the noting of an electrical signal, and“detection” is the processing of these sensed signals and noting thepresence of an arrhythmia. The timing intervals between sensed events(e.g., P-waves, R-waves, and depolarization signals associated withfibrillation which are sometimes referred to as “F-waves” or“Fib-waves”) are then classified by the microcontroller 60 by comparingthem to a predefined rate zone limit (i.e., bradycardia, normal, lowrate VT, high rate VT, and fibrillation rate zones) and various othercharacteristics (e.g., sudden onset, stability, physiologic sensors, andmorphology, etc.) in order to determine the type of remedial therapythat is needed (e.g., bradycardia pacing, antitachycardia pacing,cardioversion shocks or defibrillation shocks).

Cardiac signals are also applied to the inputs of an analog-to-digital(A/D) data acquisition system 90. The data acquisition system 90 isconfigured to acquire intracardiac electrogram signals, convert the rawanalog data into a digital signal, and store the digital signals forlater processing and/or telemetric transmission to an external device102. The data acquisition system 90 is coupled to the right atrial lead20, the coronary sinus lead 24, and the right ventricular lead 30through the switch 74 to sample cardiac signals across any pair ofdesired electrodes.

The microcontroller 60 is further coupled to a memory 94 by a suitabledata/address bus 96, wherein the programmable operating parameters usedby the microcontroller 60 are stored and modified, as required, in orderto customize the operation of the stimulation device 10 to suit theneeds of a particular patient. Such operating parameters define, forexample, pacing pulse amplitude or magnitude, pulse duration, electrodepolarity, rate, sensitivity, automatic features, arrhythmia detectioncriteria, and the amplitude, waveshape and vector of each shocking pulseto be delivered to the patient's heart 12 within each respective tier oftherapy. Other pacing parameters include base rate, rest rate andcircadian base rate.

Advantageously, the operating parameters of the implantable device 10may be non-invasively programmed into the memory 94 through a telemetrycircuit 100 in telemetric communication with the external device 102,such as a programmer, transtelephonic transceiver or a diagnostic systemanalyzer. The telemetry circuit 100 is activated by the microcontrollerby a control signal 106. The telemetry circuit 100 advantageously allowsintracardiac electrograms and status information relating to theoperation of the device 10 (as contained in the microcontroller 60 ormemory 94) to be sent to the external device 102 through an establishedcommunication link 104. In the preferred embodiment, the stimulationdevice 10 further includes a physiologic sensor 108, commonly referredto as a “rate-responsive” sensor because it is typically used to adjustpacing stimulation rate according to the exercise state of the patient.However, the physiological sensor 108 may further be used to detectchanges in cardiac output, changes in the physiological condition of theheart, or diurnal changes in activity (e.g., detecting sleep and wakestates). Accordingly, the microcontroller 60 responds by adjusting thevarious pacing parameters (such as rate, AV Delay, V-V Delay, etc.) atwhich the atrial and ventricular pulse generators, 70 and 72, generatestimulation pulses. While shown as being included within the stimulationdevice 10, it is to be understood that the physiologic sensor 108 mayalso be external to the stimulation device 10, yet still be implantedwithin or carried by the patient.

The stimulation device additionally includes a battery 110, whichprovides operating power to all of the circuits shown in FIG. 2. For thestimulation device 10, which employs shocking therapy, the battery 110must be capable of operating at low current drains for long periods oftime, and then be capable of providing high-current pulses (forcapacitor charging) when the patient requires a shock pulse. The battery110 must also have a predictable discharge characteristic so thatelective replacement time can be detected. Accordingly, the device 10preferably employs lithium/silver vanadium oxide batteries, as is truefor most (if not all) current devices. As further shown in FIG. 2, thedevice 10 is shown as having an impedance measuring circuit 112, whichis enabled by the microcontroller 60 via a control signal 114.

In the case where the stimulation device 10 is intended to operate as animplantable cardioverter/defibrillator (ICD) device, it detects theoccurrence of an arrhythmia and automatically applies an appropriateelectrical shock therapy to the heart aimed at terminating the detectedarrhythmia. To this end, the microcontroller 60 further controls ashocking circuit 116 by way of a control signal 118. The shockingcircuit 116 generates shocking pulses of low (up to 0.5 joules),moderate (0.5-10 joules), or high energy (11 to 40 joules), ascontrolled by the microcontroller 60. Such shocking pulses are appliedto the heart 12 through at least two shocking electrodes, and as shownin this embodiment, selected from the left atrial coil electrode 28, theRV coil electrode 36, and/or the SVC coil electrode 38. As noted above,the housing 40 may act as an active electrode in combination with the RVelectrode 36, or as part of a split electrical vector using the SVC coilelectrode 38 or the left atrial coil electrode 28 (i.e., using the RVelectrode as a common electrode). Cardioversion shocks are generallyconsidered to be of low to moderate energy level (so as to minimize painfelt by the patient), and/or synchronized with an R-wave and/orpertaining to the treatment of tachycardia. Defibrillation shocks aregenerally of moderate to high energy level (i.e., corresponding tothresholds in the range of 5-40 joules), delivered asynchronously (sinceR-waves may be too disorganized), and pertaining exclusively to thetreatment of fibrillation. Accordingly, the microcontroller 60 iscapable of controlling the synchronous or asynchronous delivery of theshocking pulses.

Finally, with regard to FIG. 2, microcontroller 60 includes: a cardiacischemia detection unit 101 for controlling the detection of episodes ofcardiac ischemia; hypoglycemia detection unit 103 for controlling thedetection of episodes of hypoglycemia; and a hyperglycemia detectionunit 105 for controlling the detection of episodes of hyperglycemia. Awarning unit 107 controls delivery of warning signals to the patientindicative of ischemia, hypoglycemia, or hyperglycemia. In particular,warning unit 107 controls a tickle circuit 109 that generatessubcutaneous perceptible warning signals via lead 31 (FIG. 1), which isconnected via connector 111. Device case electrodes 40 may be used asthe return electrode for the tickle warning signal. Thereafter, warningunit 107 controls a short-range telemetry system 113 to transmit warningsignals to an external handheld warning device 115 for confirmation.Additionally, a therapy control unit 117 may be provided to controltherapy based upon the detection of ischemia, hypoglycemia orhyperglycemia. The operation of these devices will be described belowwith reference to the remaining figures.

Referring to the remaining figures, flow charts, graphs and otherdiagrams illustrate the operation and novel features of stimulationdevice 10 as configured in accordance with exemplary embodiments of theinvention. In the flow charts, the various algorithmic steps aresummarized in individual “blocks”. Such blocks describe specific actionsor decisions made or carried out as the algorithm proceeds. Where amicrocontroller (or equivalent) is employed, the flow charts provide thebasis for a “control program” that may be used by such a microcontroller(or equivalent) to effectuate the desired control of the stimulationdevice. Those skilled in the art may readily write such a controlprogram based on the flow charts and other descriptions presentedherein.

Cardiac Ischemia Detection based on QTmax

FIG. 3 provides an overview of a QTmax-based cardiac ischemia detectiontechnique performed by the device of FIG. 2. Initially, at step 200,IEGM signals are received and QRS-complexes and T-waves are identifiedtherein. Then, the interval from the beginning of the QRS complex to thepeak or maximum absolute amplitude of the T-wave is calculated, at step202. This interval is referred to herein as QTmax. The Q wave of the QRScomplex may be identified as the point within the QRS complex where theIEGM signal exceeds a threshold value set based on the maximum amplitudeof the QRS complex itself. The maximum of the T-wave may be identifiedas the maximum point within a T-wave interval beginning 250 ms followingthe Q wave of the QRS complex and extending for 200 ms. These are merelyexemplary values. At step 204, the onset of a cardiac ischemia isdetected based upon detection of a significant shortening of QTmax.Routine experimentation may be performed to determine what constitutes“significant” insofar as changes in QTmax are concerned (and insofar asany other changes referred to herein as being significant areconcerned.) In one example, a 10% or greater change in a given parameteris deemed to be significant. Note that QTmax values may be derived fromeither paced or sensed events but values derived from paced and sensedevents should not be combined. In addition, QTmax varies with heart rateand so should be normalized based on heart rate. Bazettte's equation maybe used for normalizing QTmax (and for normalizing other parametersdiscussed herein.) Additionally, or in the alternative, at step 204, thedevice calculates an “ischemic burden” based on QTmax, which isrepresentative of the proportion of the time ischemia is detected. Inone example, the ischemic burden is a numerical value representative ofthe extent to and/or the time during which QTmax is shorter than itsrunning average. Steps 200-204 are preferably performed once every 30seconds.

So long as no ischemia is detected, steps 200-204 are merely repeated.If ischemia is detected, however, the patient is warned of the ischemiaby application of an internal perceptible “tickle” notification signal,at step 206. If the device is configured to generate warning signals forother conditions, such as hyperglycemia or hypoglycemia, the devicepreferably employs different notification signal frequencies for thedifferent warnings so that the patient can properly distinguish betweendifferent warnings. In addition, warning signals may be transmittedusing a short-range telemetry system to a handheld warning device usingtechniques described within the above-referenced patent application toWang et al. The handheld warning device thereby provides confirmation ofthe warning to the patient, who may be otherwise uncertain as to thereason for the internally generated tickle warning signal. Additionally,if so equipped, the device may automatically control therapy in responseto the ischemia. For example, if a drug pump is implanted within thepatient, the pump may be controlled to deliver suitableanti-thrombolytic medications directly to the patient. Implantabledevices for delivering anti-thrombolytic drugs are discussed in U.S.Pat. No. 5,960,797 to Kramer, et al. The device may also change pacingparameters in response to the detection of ischemia to, for example,deactivate overdrive pacing, which may exacerbate the ischemia. Otherforms of elevated pacing may be discontinued as well, such as AFsuppression therapy or activity-based rate responsive pacing. Varioustechniques for controlling delivery of therapy in response to ischemiaare discussed U.S. Pat. No. 6,256,538 to Ekwall, listed above. See alsoU.S. Pat. No. 6,377,852 to Bomzin et al., which provides techniques forslowing the heart rate in response to ischemia. In addition, if thedevice is an ICD, then it may be controlled to immediately begincharging defibrillation capacitors in expectation of delivery of adefibrillation shock, which may be needed if the ischemia triggers VF.

Hence, FIG. 3 provides an overview of technique that seeks to detect theonset of cardiac ischemia based primarily on changes in QTmax. As willbe explained below, additional parameters of the IEGM signal, such as STdeviation, may be employed to confirm the detection made based uponQTmax. Insofar as the detection of T-waves at step 200 is concerned, theinvention may exploit techniques set forth in U.S. Patent ApplicationSerial Number 2004/0077962 of Kroll, published Apr. 22, 2004, entitled“System and Method for Monitoring Blood Glucose Levels Using anImplantable Medical Device.” Certain techniques described therein areparticularly well suited for detecting T-waves with a high degree ofaccuracy to permit precise detection of features of the T-wave (such asits peak) so as to achieve more precise measurement of QRS/T-waveintervals. The patent application to Kroll is fully incorporated byreference herein. The invention also may exploit T-wave detectiontechniques set forth within the aforementioned patent application to Minet al., which help prevent P-waves from being misinterpreted as T-waveson unipolar sensing channels.

FIG. 4 illustrates the QTmax interval. Briefly, the figure provides astylized representation of an exemplary IEGM trace 208 for a singleheartbeat for a patient suffering myocardial ischemia. The stylizedrepresentation of the IEGM signal of FIG. 4 is provided for illustrativepurposes and should not be construed as an actual, clinically detectedIEGM signal. The heartbeat includes a P-wave 210 representative of anatrial depolarization, a QRS complex 212 representative of a ventriculardepolarization and a T-wave 214 representative of ventricularrepolarization. The QRS complex itself is defined by points Q, R, and S.Q represents the beginning of the complex; R represents the peak of thecomplex; and S represents the end of the complex. In the examplesdescribed and illustrated herein, the aforementioned QTmax interval isspecified as the time interval from point Q to the peak or maximumamplitude point of T-wave. However, QTmax may alternatively becalculated based on other points or features of the QRS complex, such asthe R point or the S point of the complex, so long as the calculationsare consistent. As it is used herein, the “Q” of QTmax generally refersto the QRS complex and not specifically to the Q point of the QRScomplex. Hence, the term QTmax encompasses RTmax as one example andSTmax as another example. Also, in the particular example of FIG. 4, thepeak of the T-wave is positive, i.e. it is greater than a baselinevoltage of the IEGM signal. This need not be the case. In otherexamples, the peak has a negative value with respect to a baseline ofthe IEGM signal. The polarity of the entire signal may also be reversed.Herein, the peak or maximum amplitude of T-wave refers to the peak ormaximum of the absolute value of the difference between the T-wavevoltage and the baseline voltage of the IEGM signal. The baselinevoltage 216 may be measured during an interval prior to the P-wave, asshown. The interval may be, for example, 50 milliseconds (ms) induration, beginning 100 ms prior to the P-wave. Alternatively, theinterval may be timed relative to the QRS complex. If timed relative tothe QRS complex, the interval may commence 250 ms prior to the R wave ofthe QRS complex. Also alternatively, a single detection point may beused, rather than a detection interval.

FIG. 5 illustrates change in QTmax brought on by acute myocardialischemia. A first exemplary IEGM trace 218 represents a heartbeat ofhealthy patient, i.e. one not subject to cardiac ischemia, hypoglycemiaor hyperglycemia. A second trace 220 illustrates the heartbeat for apatient suffering an acute myocardial ischemia. The traces are IEGMsignals derived from voltage differences between the tip of a rightventricular (RV) lead and the device case. Note first that the IEGMtrace for the healthy patient exhibits a T-wave that is reversed inpolarity with respect to T-wave of the patient suffering the ischemia.T-wave inversion is typical during ischemia as well as during otherconditions such as electrolyte abnormalities, which influencerepolarization. Therefore, FIG. 5 illustrates that the QTmax feature isvalid even in the presence of a T-wave inversion. In any case, for thepurposes of ischemia detection, the peak of the T-wave during ischemiaoccurs earlier than the corresponding peak without ischemia. In otherwords, QTmax during ischemia 222 is shorter than QTmax without ischemia224. Hence, a large positive value of ΔQTmax (226) is observed, whereΔQTmax represents the amount of the reduction in QTmax. A negative valueof ΔQTmax is associated with an increase in interval length. In theexample FIG. 5, ΔQTmax is represented as a positive number. Note thatsignificant negative ΔQTmax intervals may also be observed which, aswill be explained below, are instead indicative of hypoglycemia.

ΔQTmax is the value used to detect the onset of ischemia. Preferably,any change in QTmax from a current baseline value is tracked. In oneexample, the device tracks a running average of QTmax intervals (derivedfrom sensed events and normalized based on heart rate) for use as abaseline value. Different baseline values may be calculated fordifferent heart rate ranges. In any case, for each new heartbeat, thedevice compares the QTmax interval for that heartbeat against theappropriate baseline to calculate ΔQTmax for that heartbeat. ΔQTmaxvalues are averaged over, e.g., eight to sixteen heartbeats and thencompared against a predetermined QTmax-based threshold. If the averageexceeds the threshold, cardiac ischemia is thereby indicated. Thethreshold is a programmable value set, for example, based upon apercentage of the running average of the QTmax interval. In one specificexample, if ΔQTmax is a positive value, which exceeds 10% of the runningaverage of the QTmax intervals, cardiac ischemia is thereby indicated(i.e. QTmax has been found to be reduced by 10%). Otherwise conventionalthreshold comparison techniques may be employed for use with ΔQTmax. Inanother example, rather than comparing an average based on eight tosixteen values to the threshold, the occurrence of only a single ΔQTmaxvalue exceeding the threshold is indicative of ischemia. In yet anotherexample, if ΔQTmax exceeds the threshold for three out of fiveheartbeats, ischemia is indicated. Multiple thresholds may be defined,if desired, to trigger warning signals indicative of different levels ofurgency. For example, if ΔQTmax exceeds a first, lower threshold, awarning signal indicative of a moderate ischemia is issued. If ΔQTmaxexceeds a higher threshold, a second warning signal indicative of a moreserious ischemia is issued. As can be appreciated, a wide variety ofspecific implementations maybe provided in accordance with the generaltechniques described herein. Routine experimentation may be performed todetermine appropriate threshold levels.

Hence, FIGS. 3-5 provide an overview of techniques for detecting theonset of cardiac ischemia based on changes in the QTmax interval. Aswill be explained below, particularly with reference to FIG. 13, STdeviation may be used to corroborate any cardiac ischemia detection madebased upon QTmax intervals. Other parameters may be used as well tocorroborate the detection of cardiac ischemia, including postT-wave-based detection parameters described in the above-referencedpatent application to Wang et al. and T-wave energy-based parameters andT-wave slope-based parameters described in the above-referenced patentapplication Min et al.

Cardiac Ischemia Detection based on ST deviation and QTend

FIG. 6 provides an overview of a QTend-based cardiac ischemia detectiontechnique performed by the device of FIG. 2. Many aspects of thetechnique are similar to those of the technique of FIG. 3 and will notbe described again in detail. Initially, at step 300, IEGM signals arereceived and QRS-complexes and T-waves are identified therein. Then, theinterval from the beginning of the QRS complex to the end of the T-waveis calculated, at step 302. This interval is referred to herein asQTend. In the examples described and illustrated herein, the QTendinterval is specified as the time interval from point Q of the QRScomplex to the end point of the T-wave. However, as with QTmax, QTendmay alternatively be calculated based on other points or features of theQRS complex, such as the R point or the S point of the complex, so longas the calculations are consistent. The elevation of the interval fromthe end of the QRS complex to the beginning of the T-wave is alsocalculated, at step 304. This interval is referred to herein as the STsegment, its elevation is referred to as the ST elevation, and changesin the ST elevation is the ST deviation. Otherwise conventionaltechniques for detecting ST segment elevation may be used. Detection ofST segment elevation is discussed, for example, in U.S. Pat. Nos.6,016,443 and 6,256,538 to Ekwall, listed above. At step 306, the onsetof a cardiac ischemia is detected based upon observation of asignificant deviation in the ST segment along with little or no changein QTend. A deviation in the ST is preferably calculated as a change inthe average amplitude of the ST segment. Since the polarity of the IEGMsignal is arbitrary, this may, in some cases, represent an increase involtage of the ST segment and in other cases a decrease in voltage. Itis the change in ST segment elevation that is important. As before, datafrom paced and sensed events should not be combined. QTend values shouldbe normalized based on heart rate. Moreover, ST segments may bereferenced beat-by-beat to either the PQ or TP regions of the IEGM.

Additionally, or in the alternative, at step 304, the device calculatesan ischemic burden based on ST deviation and QTend, which isrepresentative of the risk of ischemia. In one example, the ischemicburden is a single metric value derived from ST deviation and changes inQTend. Techniques for combining different parameters into a singlemetric value are set forth in published U.S. Patent Application2004/0138716, to Koh et al., entitled “System and Method for DetectingCircadian States Using an Implantable Medical Device,” published Jul.15, 2004. If QTend and ST deviation are measured for diagnostic purposesonly, steps 300-306 are preferably performed once an hour to calculatedand record the ischemic burden. If measured for detecting ischemia,steps 300-306 are preferably performed more often, e.g. once every 30seconds. In any case, so long as no ischemia is detected, steps 300-306are merely repeated. If ischemia is detected, however, the patient iswarned of the ischemia, at step 308, and, if so equipped, the deviceautomatically controls therapy in response to the ischemia. If thedevice is an ICD, it may be controlled to immediately begin chargingdefibrillation capacitors.

Hence, FIG. 6 provides an overview of technique that seeks to detect theonset of cardiac ischemia based on a combination of ST deviation andQTend. Additional parameters of the IEGM signal, such as theaforementioned QTmax interval, may be employed to confirm the detection.FIG. 7 illustrates ST segment elevation and the QTend interval. Briefly,FIG. 7 provides a stylized representation of an exemplary IEGM trace 310for a single heartbeat for a patient suffering a myocardial ischemia.The ST segment 312 is the interval from the end of the QRS complex tothe start of the T-wave. The duration of this interval is not ofinterest in this technique. However, its deviation, i.e. the extent towhich its elevation changes over time is of interest. To calculate theelevation of an individual ST segment deviation, the device identifies awindow 316 with the ST segment. The elevation of the ST segment(relative to a baseline voltage) within the window is denoted byreference numeral 318. The ST segment elevation may be measured during aspecified interval following the QRS complex, as shown. The interval maybe, for example, 50 ms in duration, beginning 50 ms following the R waveof the QRS complex. For ventricular paced events, the interval maybegin, for example, 80 ms following a V-pulse and extend for 50 ms.These are merely exemplary values. The elevation may be quantified basedon the mean of the ST segment sample. Meanwhile, the QTend interval isthe time interval between the beginning of the QRS complex and the endpoint of the T-wave, i.e. the point at which the slope of the T-wavefollowing its peak becomes substantially flat. Techniques for detectingT-wave slope are set forth in the aforementioned patent application toMin et al. The QTend interval is denoted by reference numeral 321.

FIG. 8 illustrates changes in ST segment elevation brought on by acutemyocardial ischemia. A first exemplary IEGM trace 320 represents aheartbeat of a healthy patient, i.e. one not subject to cardiac ischemiaor hypo/hyperglycemia. A second trace 322 illustrates the heartbeat fora patient suffering an acute myocardial ischemia. As with other tracesillustrated herein, the IEGM signals of FIG. 8 are exemplaryrepresentations of IEGM signals provided for illustrative purposes only.Comparing the two traces, the elevation of the ST-segment duringischemia (323) is much greater than the elevation of the ST-segmentwithout ischemia (325), i.e. there is a significant ST deviation.However, there is little or no change in QTend, i.e. the absolute valueof ΔQTend is substantially zero, where ΔQtend represents the amount ofthe reduction, if any, in QTend interval duration. (A positive value ofΔQTmax is associated with a decrease in interval length. A negativevalue of ΔQTmax is associated with an increase in interval length. Forthe purposes of the technique of FIG. 6, only the magnitude of anychange in QTend is important.) Hence, QTend helps corroborate thedetection of ischemia made based on ST deviation. In particular, as willbe explained in more detail below with reference to FIGS. 9-10, a changein ST segment elevation brought on by hypoglycemia will additionallytrigger a significant increase in QTend. Hence, without an examinationof QTend, it may not be possible to reliably distinguish a change in STsegment elevation caused by ischemia from a change caused byhypoglycemia.

Preferably, any changes in the ST segment elevation and in QTend fromcurrent baseline values are tracked. In one example, the device tracks arunning average of the ST segment elevation (as derived from sensedevents) and then, for each new heartbeat, the device compares the STsegment elevation for that heartbeat against the running average tocalculate a ST deviation value for that heartbeat. Note that ST segmentvalues need not be normalized based on heart rate. The device alsotracks a running average of the QTend interval (as derived from sensedevents and normalized based on heart rate) and then, for each newheartbeat, compares the QTend interval for that heartbeat against therunning average to calculate a ΔQTend value for that heartbeat. Thevalue of ST deviation for the heartbeat is averaged over, e.g., eight tosixteen heartbeats and compared against a predetermined deviation-basedthreshold. If the average exceeds the threshold, then the absolute valueof ΔQTend is also averaged over eight to sixteen heartbeats and comparedagainst a predetermined ΔQTend-based threshold. If ST deviation exceedsits respective threshold (indicating a significant change in ST segmentelevation), but the absolute value of ΔQTend does not exceed itsrespective threshold (indicating little or no change in QTend), thencardiac ischemia is thereby indicated. (If ST deviation exceeds itsrespective threshold and the absolute value of ΔQTend also exceeds itsrespective threshold, an indication of hypoglycemia may instead beprovided. See FIG. 13, discussed below.)

The various thresholds are programmable values set, for example, basedupon respective running averages. In one specific example, the thresholdfor ΔQTend is set to 10% of the running average of the QTend intervals.The threshold for ST deviation may be set, for example, based on somepercentage (e.g. 20%) of a running average of peak-to-peak voltageswings in QRS complexes, i.e. based on a percentage of the averagedifference from a maximum positive voltage to a maximum negative voltagewithin each QRS complex. Alternatively, the threshold for ST deviationmay be set to a preset voltage difference, such as 0.25-0.5 milli-Volts(mV). As with the QTmax-based technique, alternative thresholdcomparison techniques may instead be used. Multiple thresholds may bedefined, in some implementations, to trigger warning signals indicativeof different levels of urgency. Routine experimentation may be performedto determine appropriate threshold levels.

Hence, FIGS. 6-8 provide an overview of techniques for detecting theonset of cardiac ischemia based on an examination of ST segmentdeviation in conjunction with QTend interval. Other parameters may beused to further corroborate the detection of cardiac ischemia, such asthe QTmax interval and parameters described in the above-referencedpatent applications to Wang et al. and Min et al. In the next section,techniques for detecting hypoglycemia will be described.

Hypoglycemia Detection based on QTmax and/or QTend

FIG. 9 provides an overview of hypoglycemia detection techniquesperformed by the device of FIG. 2. Many aspects of this technique aresimilar to those of the ischemia detection techniques described aboveand will not be described again in detail. Initially, at step 400, IEGMsignals are received and QRS-complexes and T-waves are identifiedtherein. Then, at step 402, QTmax and QTend intervals are measured. Atstep 404, the onset of hypoglycemia is detected based upon observationof a significant lengthening of either QTend or QTmax or both. In thisregard, both QTmax and QTend increase due to hypoglycemia. Hence, one orthe other is sufficient to detect hypoglycemia. Both are preferred toenhance detection reliability. A change in ST segment elevation may beused to further corroborate the detection (see FIG. 13). As before, datafrom paced or sensed events should not be combined. QTmax and QTendintervals should be normalized based on heart rate.

Additionally, or in the alternative, ST deviation, QTmax and QTend maybe stored for diagnostic purposes. The device may calculate a singlevalue representative of the risk of hypoglycemia based on a combinationof ST deviation, QTmax and QTend, similar to the ischemic burdendiscussed above. In any case, so long as hypoglycemia is not detected,steps 400-404 are merely repeated. If hypoglycemia is detected, however,the patient is warned, at step 406. Preferably, the warning signaldiffers from the one generated for ischemia. If so equipped, the devicemay automatically initiate therapy appropriate for responding tohypoglycemia. For example, if an insulin pump is implanted within adiabetic patient, the pump may be controlled to adjust the dosage ofinsulin in response to hypoglycemia. Techniques for controlling deliveryof therapy in response to hypoglycemia are set forth in the PatentApplication of Kroll, incorporated by reference above. Informationregarding implantable insulin pumps may be found in U.S. Pat. No.4,731,051 to Fischell and in U.S. Pat. No. 4,947,845 to Davis.

Hence, FIG. 9 provides an overview of technique that seeks to detect theonset of hypoglycemia based on a lengthening of QTmax or QTend. FIG. 10illustrates QTmax and QTend brought on by hypoglycemia, as well aschanges in ST segment deviation. A first exemplary IEGM trace 410represents a heartbeat of a healthy patient, i.e. one not subject tohypo/hyperglycemia or cardiac ischemia. A second trace 412 illustratesthe heartbeat for a patient suffering from hypoglycemia. As with othertraces illustrated herein, the IEGM signals of FIG. 10 are exemplaryrepresentations of IEGM signals provided for illustrative purposes only.Comparing the two traces, there is a significant lengthening of bothQTmax and QTend, i.e. both ΔQTmax and ΔQTend are large in magnitude. (Asexplained above, ΔQTmax and ΔQTend are defined as positive numbers for areduction in interval length and as negative numbers for an increase ininterval length.)

Hence, an increase in either QTmax or QTend or both allows the device todetect hypoglycemia. ST deviation may be used to corroborate thedetermination. As can be seen from FIG. 10, the deviation of the STsegment changes in response to hypoglycemia. Preferably, any changes inQTmax and/or QTend are measured with respect to baseline values of thoseparameters. In one example, the device tracks running averages QTmax andQTend (as derived from sensed events and normalized based on heart rate)fro use as baseline values. Different baseline values may be calculatedfor different heart rate ranges. Then for each new heartbeat, the devicecompares new values for those parameters against the appropriatebaseline values to calculate ΔQTmax and ΔQTend values for thatheartbeat. In the example, the ΔQTmax and ΔQTend values are averagedover eight to sixteen heartbeats. ΔQTmax is compared against apredetermined ΔQTmax-based threshold and ΔQTend is compared against apredetermined ΔQTend-based threshold and. These thresholds may differ invalue from the corresponding thresholds discussed above. If ΔQTmax andΔQTend both exceed their respective thresholds, an indication ofhypoglycemia is thereby provided. The various thresholds areprogrammable values set, for example, based upon percentages of runningaverages of the respective interval. Again, multiple thresholds may bedefined, if desired, to trigger warning signals indicative of differentlevels of urgency. Routine experimentation may be performed to determineappropriate threshold levels. In the next section, techniques forinstead detecting hyperglycemia will be described.

Hyperglycemia Detection Based on ST Deviation, QTmax and QTend

FIG. 11 provides an overview of hyperglycemia detection techniquesperformed by the device of FIG. 2. Many aspects of this technique aresimilar to those of the detection techniques described above and willnot be described again in detail. Initially, at step 500, IEGM signalsare received and QRS-complexes and T-waves are identified therein. Then,at step 502, QTmax intervals are measured and, at step 504, ST segmentelevation is detected. At step 506, the onset of a hyperglycemia isdetected based upon detection of a significant change in ST segmentelevation along with little or no change in QTmax. A change in STsegment elevation along with a shortening of QTmax is instead indicativeof cardiac ischemia. Note that, with hyperglycemia, neither QTmax norQTend changes significantly. However, a change in ST segment elevationalong with little or no change in QTend may also be indicative of eitherhyperglycemia or cardiac ischemia. So QTmax is observed instead ofQTend. As before, data from paced and sensed events should not becombined. QTmax and QTend intervals should be normalized based on heartrate.

Additionally, or in the alternative, values representative of STdeviation, QTmax and QTend may be stored for diagnostic purposes. Thedevice may calculate a single value representative of the risk ofhyperglycemia based on a combination of ST deviation, QTmax and QTend,similar to the ischemic burden discussed above. In any case, so long ashyperglycemia is not detected, steps 500-506 are merely repeated. Ifhyperglycemia is detected, however, the patient is warned, at step 508,and, if properly equipped, the device automatically controls therapyappropriate for responding to hyperglycemia. If an insulin pump isimplanted, the pump may be controlled to adjust the dosage of insulin inresponse to hyperglycemia. Techniques set forth in the patentapplication of Kroll, listed above, may be suitable for this purpose.

Hence, FIG. 11 provides an overview of a technique that seeks to detectthe onset of hyperglycemia based on a combination of ST deviation andQTmax. FIG. 12 illustrates changes in ST segment elevation brought on byhyperglycemia. A first exemplary IEGM trace 510 represents a heartbeatof a healthy patient, i.e. one not subject to hypo/hyperglycemia orcardiac ischemia. A second trace 512 illustrates the heartbeat for apatient with hyperglycemia. As with other traces illustrated herein, theIEGM signals of FIG. 12 are exemplary representations of IEGM signalsprovided for illustrative purposes only. Comparing the two traces, theelevation of the ST-segment changes. However, there is little or nochange in QTmax, i.e. an absolute value of ΔQTmax is near zero. (Thereis also little or no change in QTend during hyperglycemia, i.e. anabsolute value of ΔQTend is also near zero.)

Hence, an examination of QTmax allows the device to properly distinguisha change in ST segment elevation due to hyperglycemia from a change dueto hypoglycemia or cardiac ischemia. Compare FIG. 12 with FIGS. 5, 8 and10, described above. Preferably, any changes in ST segment elevation (asderived from sensed events) and QTmax (as derived from sensed events andnormalized based on heart rate) are measured with respect to baselinevalues of those parameters and values for ST deviation and ΔQTmax arecalculated for each heartbeat and averaged over multiple heartbeats. Theaveraged values are compared against respective thresholds. A warning ofhyperglycemia is issued only if ST deviation exceeds its thresholdwhereas ΔQTmax remains below its thresholds. These thresholds may differin value from corresponding thresholds discussed above. The variousthresholds are programmable values set, for example, based uponrespective running averages. Again, multiple thresholds may be defined,in some implementations, to trigger warning signals indicative ofdifferent levels of urgency. Routine experimentation may be performed todetermine appropriate threshold levels.

What have been described thus far are various techniques for detectingcardiac ischemia, hypoglycemia or hyperglycemia based on variouscombinations of QTmax, QTend and ST deviation. Preferably, the device isconfigured to detect any of these conditions and to distinguishtherebetween. This is discussed in the following section.

Combined Hypo/Hyperglycemia and Ischemia Detection Examples

FIG. 13 illustrates an exemplary technique for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia wherein QTmax, QTendand ST deviation are each examined. Beginning at step 600, the implanteddevice receives IEGM signals and detect QRS complexes and T-waves. Atstep 602, the device determines ST segment elevation, QTmax and QTendfor each individual heartbeat (as derived from either sensed events onlyor paced events only and properly normalized based on heart rate). Basedupon these values, the device detects and distinguishes between cardiacischemia, hypoglycemia and hyperglycemia. Briefly, at steps 604-606, thedevice detects cardiac ischemia based upon any significant change in STsegment elevation (i.e. a significant value for ST deviation) combinedwith a concurrent shortening of QTmax, so long as there is also littleor no change in QTend. At step 608-610, the device detects hypoglycemiabased upon any significant change in ST segment elevation combined witha lengthening of both QTmax and QTend. At steps 612-614, the devicedetects hyperglycemia based upon a significant change in ST segmentelevation so long as there is little or no change in either QTmax orQTend. Appropriate warning signals are issued upon detection ofischemia, hypoglycemia or hyperglycemia. The above-describedthreshold-based techniques may be employed to make these variousdeterminations. Note that the conditions set forth in the steps 604, 608and 612 are listed above in Table I.

If none of the conditions set forth in steps 604, 608 and 612 are met,then no indication of ischemia, hypoglycemia or hyperglycemia is made,step 616, and processing instead returns to step 604 for examination ofadditional IEGM signals. In other words, no warning of ischemia,hypoglycemia or hyperglycemia is triggered unless each of the threeparameters (ST deviation, QTmax and QTend) corroborates the diagnosis.This differs from the individual examples discussed above wherein anindication of ischemia, hypoglycemia or hyperglycemia may be made basedupon significant changes in only one or two of the parameters. Byexamining all three parameters, a greater degree of reliability andspecificity is achieved. Additional detection parameters may be examinedas well, including otherwise conventional detection parameters or theparameters set forth in the aforementioned patent applications to Wanget al. and Min et al. IN any case, once the analysis is completeappropriate warnings are issued and therapy is adjusted.

FIG. 14 illustrates an exemplary technique for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on just QTmax andST segment elevation. Beginning at step 700, the implanted deviceevaluates ST segment elevation and ΔQTmax. If there is no substantialchange in ST elevation, i.e. ST deviation is small, then the patient'scondition is deemed to be normal, at step 702. However, if there hasbeen a substantial change in ST elevation, then the device proceeds todetermine whether there has also been a substantial change in QTmax,i.e. whether ΔQTmax exceeds a threshold representative of a significantchange. If not, then hyperglycemia is suggested, at step 704. If ΔQTmaxexceeds the threshold, however, the device determines whether QTmax haslengthened or shortened. If QTmax has lengthened, then hypoglycemia issuggested that step 706. If QTmax has become shorter, then ischemia issuggested that step 708. The above-described threshold-based techniquesmay be employed to make these various determinations. Appropriatewarning signals are issued and therapy is adjusted.

FIG. 15 illustrates an exemplary technique for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on just QTend andST segment elevation. Beginning at step 800, the implanted deviceevaluates ST segment elevation and ΔQTend. As before, if there is nosubstantial change in ST elevation, i.e. ST deviation is small, then thepatient's condition is deemed to be normal, at step 802. If there hasbeen a substantial change in ST elevation, then the device proceeds todetermine whether there has also been a substantial change in QTend,i.e. whether ΔQTmax exceeds a threshold representative of a significantchange. If not, then ischemia or hyperglycemia are suggested, at step804, and further analysis may need to be performed to distinguishtherebetween (such as by examining QTmax). If ΔQTend exceeds thethreshold, however, the device then determines whether QTend haslengthened or shortened. If QTend has lengthened, then hypoglycemia issuggested that step 806. If QTend has instead become shorter, then theanalysis is indeterminate, at step 808, perhaps indicative of erroneousdata. As already explained, a significant change in ST segment elevationin combination with a significant change in QTend should be associatedwith lengthening of QTend, not a reduction in QTend. Accordingly, nowarnings are issued.) Assuming the analysis is not indeterminate,appropriate warning signals are issued and therapy is adjusted.

In general, a wide variety of techniques can be implemented consistentwith the principles the invention and no attempt is made herein todescribe all possible techniques. Although described primarily withreference to an example wherein the implanted device is adefibrillation/pacer, principles of the invention are applicable toother implantable medical devices as well. In addition, whereas thetechniques described herein are performed by the implanted device, thetechniques may alternatively be performed by an external device usingIEGM signals or other signals transmitted from the implanted device. Forexample, a bedside monitor may be configured to receive IEGM signalsfrom the implanted device via “long-range” telemetry then analyze thesignals using the aforementioned techniques and issue any appropriatewarnings. Alternatively, the bedside monitor may transmit the IEGM datato a central server or other central processing device, which analyzesdata from multiple patients to detect ischemia, hypoglycemia orhyperglycemia within any of those patients. In such an implementation,the central processing device then transmits appropriate warning signalsto the bedside monitor of the patient for warning the patient and thenadditionally transmits appropriate warning signals to the physicianassociated with the patient or a third party such as emergency medicalservice (EMS) personnel. A system incorporating bedside monitoring unitsconnected to a centralized external programmer system is described inU.S. Patent Application Serial Number 2002/0143372, of Snell et al.,entitled “System and Method for Remote Programming of ImplantableCardiac Stimulation Devices,” published Oct. 3, 2002.

The various functional components of the exemplary systems describedherein may be implemented using any appropriate technology including,for example, microprocessors running software programs or applicationspecific integrated circuits (ASICs) executing hard-wired logicoperations. The exemplary embodiments of the invention described hereinare merely illustrative of the invention and should not be construed aslimiting the scope of the invention.

1. A method for use with an implantable medical device for detectingcardiac ischemia in a patient in which the device is implanted, themethod comprising: tracking repolarization peak-based intervalsrepresentative of intervals between depolarization events and peaks ofcorresponding repolarization events within electrical cardiac signals;tracking repolarization end-based intervals representative of intervalsbetween depolarization events and ends of corresponding repolarizationevents within electrical cardiac signals; and detecting an episode ofcardiac ischemia based on the combination of a decrease in therepolarization peak-based intervals and a lack of significant change indurations of the repolarization end-based intervals.
 2. The method ofclaim 1 wherein the repolarization peak-based intervals arerepresentative of intervals between QRS complexes and peaks ofcorresponding T-waves (QTmax intervals).
 3. The method of claim 1further including the step of tracking patient heart rate and whereinthe repolarization peak-based intervals are normalized based on heartrate.
 4. The method of claim 1 wherein the step of trackingrepolarization peak-based intervals is performed to track a baselineinterval based on a moving average; and wherein the step of detecting anepisode of cardiac ischemia based on a significant decrease in therepolarization peak-based intervals is performed to detect a decreaserelative to the baseline interval.
 5. The method of claim 1 wherein thestep of detecting an episode of cardiac ischemia based on a decrease inthe repolarization peak-based intervals includes the step of determiningif the decrease exceeds a predetermined repolarization peak-basedcardiac ischemia detection threshold.
 6. The method of claim 1 furtherincluding the step of recording diagnostic information representative ofthe repolarization peak-based intervals.
 7. The method of claim 6wherein the diagnostic information includes an ischemic burden derivedfrom the repolarization peak-based intervals.
 8. The method of claim 1further including the step of controlling therapy in response to thedetection of an episode of cardiac ischemia.
 9. The method of claim 8wherein an implantable drug pump is provided and wherein the step ofcontrolling therapy in response to the detection of an episode ofcardiac ischemia includes the step of delivering anti-thromboticmedications to the patient using the drug pump.
 10. The method of claim8 wherein an implantable cardiac stimulation device is provided andwherein the step of delivering therapy in response to the detection ofan episode of cardiac ischemia includes the step of reducing a pacingrate employed by the stimulation device.
 11. The method of claim 1wherein an implantable cardiac defibrillation device is provided withdefibrillation shock capacitors and wherein the capacitors are chargedin response to the detection of an episode of cardiac ischemia.
 12. Themethod of claim 1 further including the step of generating a warningsignal in response to detection of an episode of cardiac ischemia. 13.The method of claim 12 wherein an implantable warning device is providedand wherein the step of generating a warning signal includes the step ofdelivering a perceptible warning signal to the patient via theimplantable warning device.
 14. The method of claim 12 for use with anexternal warning device and wherein the step of generating a warningsignal includes the step of transmission control signals to the externalwarning device for controlling the external device to generate warningsignals for warning the patient.
 15. The method of claim 1 furtherincluding the steps of: tracking ST segments representative of segmentsof the cardiac signals between depolarization events and correspondingrepolarization events; and confirming detection of an episode of cardiacischemia based on a change in elevation of the ST segments.
 16. A systemfor use with an implantable medical device for detecting cardiacischemia in a patient in which the device is implanted comprising: atiming unit operative to track repolarization peak-based intervalsrepresentative of intervals between depolarization events and peaks ofcorresponding repolarization events within electrical cardiac signalsand to track repolarization end-based intervals representative ofintervals between depolarization events and ends of correspondingrepolarization events within electrical cardiac signals; and a cardiacischemia detection unit operative to detect an episode of cardiacischemia based on the combination of a decrease in the repolarizationpeak-based intervals and a lack of significant change in durations ofthe repolarization end-based intervals.